Owing to the development of therapeutics using antibiotics, diseases caused by bacteria have been overcome for the most part. There are, however, still some serious problems to be solved in the field of therapeutics of infectious diseases caused by bacteria. For example, Nosocomial infections caused by methicillin-resistant Staphylococcus aureas (MRSA) have become a very serious clinical problem. MRSA has developed resistance to most .beta.-lactam antibiotics as well as numerous other antibiotics due to the presence of the mec A gene. MRSA produces an altered penicillin-binding protein, PBP2a, for which most clinically significant .beta.-lactam antibiotics have low affinity. A desperate search has very recently been initiated to find so-called fourth generation cephalosporins that possess affinity for PBP2a. Screening programs aimed at discovering new structural drug motifs that are efficacious against MRSA have therefore become increasingly significant.
Recently, four new compounds identified as TAN-1057A-D were isolated from Flexibacter sp. PK-74 and PK-176. See, U.S. Pat. No. 4,971,965; Katayama, et al., The Journal of Antibiotics, 1993, 606-613 and Funabashi, et al., Tetrahedron 1993, 49, 13-28. These have the structures shown hereinbelow. ##STR1## These compounds were found to be dipeptide antibiotics with potent activity against MRSA. TAN-1057A-D displayed better activity against Gram-positive bacteria than against Gram-negative bacteria. TAN-1057A and D, which have the S-configuration in the heterocyclic portion of the molecule, were more active than TAN-1057 B and C which possess the R-configuration. There was no cross-resistance between TAN-1057 and methicillin, erythromycin and gentamycin. TAN-1057A was shown to display potent activity against all of the MRSA strains evaluated and was found to compare very favorably to vancomycin in mice.
TAN-1057A and B are dipeptides consisting of .beta.-homoarginine and a unique heterocyclic amidinourea derivative of 2,3-diaminopropionic acid. TAN-1057 A and B gradually lost their antibacterial activities in basic aqueous solutions due to hydrolytic opening of the six-membered ring system (Scheme 1). Hydrolysis of TAN-1057 A occurs in both acidic and basic media, and affords the acyclic form (5) with attendant racemization of the .alpha.-amino acid stereogenic center. It was also reported that the acyclic form of the molecule can be converted back into the cyclic form via the methyl ester intermediate resulting in a diastereomer mixture (1:1) of TAN-1057A and B. ##STR2##
Both TAN-1057C and TAN-1057D have a 7-membered heterocyclic ring; however, they are labile substances that were reported to rapidly convert to a mixture of TAN-1057A/B upon standing in water.
There are the only a few compounds that to date are known to be effective antibiotics against infections caused by MRSA. Furthermore, to date, no one heretofore has synthesized any of the TAN-1057A-D compounds; they have only been isolated from the Flexibacter strain in the soil.
The present inventors, however, have not only found other drugs that are useful antibiotics against bacterial infections, including those caused by MRSA, but also have developed synthetic methods for preparing these compounds, including TAN-1057A-D.